Systems analysis identifies melanoma-enriched pro-oncogenic networks controlled by the RNA binding protein CELF1

Metehan Cifdaloz; Lisa Osterloh; Osvaldo Graña; Erica Riveiro-Falkenbach; Pilar Ximénez-Embún; Javier Muñoz; Cristina Tejedo; Tonantzin G. Calvo; Panagiotis Karras; David Olmeda; Belén Miñana; Gonzalo Gómez-López; Estela Cañon; Eduardo Eyras; Haihong Guo; Ferdinand Kappes; Pablo L. Ortiz-Romero; Jose L. Rodríguez-Peralto; Diego Megías; Juan Valcárcel; María S. Soengas

doi:10.1038/s41467-017-02353-y

Systems analysis identifies melanoma-enriched pro-oncogenic networks controlled by the RNA binding protein CELF1

Metehan Cifdaloz, Lisa Osterloh, Osvaldo Graña, Erica Riveiro-Falkenbach, Pilar Ximénez-Embún, Javier Muñoz, Cristina Tejedo, Tonantzin G. Calvo, Panagiotis Karras, David Olmeda, Belén Miñana, Gonzalo Gómez-López, Estela Cañon, Eduardo Eyras, Haihong Guo, Ferdinand Kappes, Pablo L. Ortiz-Romero, Jose L. Rodríguez-Peralto, Diego Megías, Juan ValcárcelMaría S. Soengas^*

^*Corresponding author for this work

Department of Biosciences and Bioinformatics

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

Abstract

Melanomas are well-known for their altered mRNA expression profiles. Yet, the specific contribution of mRNA binding proteins (mRBPs) to melanoma development remains unclear. Here we identify a cluster of melanoma-enriched genes under the control of CUGBP Elav-like family member 1 (CELF1). CELF1 was discovered with a distinct prognostic value in melanoma after mining the genomic landscape of the 692 known mRBPs across different cancer types. Genome-wide transcriptomic, proteomic, and RNA-immunoprecipitation studies, together with loss-of-function analyses in cell lines, and histopathological evaluation in clinical biopsies, revealed an intricate repertoire of CELF1-RNA interactors with minimal overlap with other malignancies. This systems approach uncovered the oncogene DEK as an unexpected target and downstream effector of CELF1. Importantly, CELF1 and DEK were found to represent early-induced melanoma genes and adverse indicators of overall patient survival. These results underscore novel roles of CELF1 in melanoma, illustrating tumor type-restricted functions of RBPs in cancer.

Original language	English
Article number	2249
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02353-y
Publication status	Published - 1 Dec 2017

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10.1038/s41467-017-02353-y

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Cifdaloz, M., Osterloh, L., Graña, O., Riveiro-Falkenbach, E., Ximénez-Embún, P., Muñoz, J., Tejedo, C., Calvo, T. G., Karras, P., Olmeda, D., Miñana, B., Gómez-López, G., Cañon, E., Eyras, E., Guo, H., Kappes, F., Ortiz-Romero, P. L., Rodríguez-Peralto, J. L., Megías, D., ... Soengas, M. S. (2017). Systems analysis identifies melanoma-enriched pro-oncogenic networks controlled by the RNA binding protein CELF1. Nature Communications, 8(1), Article 2249. https://doi.org/10.1038/s41467-017-02353-y

@article{76db4dfc253f42c39320e8458ec4074a,

title = "Systems analysis identifies melanoma-enriched pro-oncogenic networks controlled by the RNA binding protein CELF1",

abstract = "Melanomas are well-known for their altered mRNA expression profiles. Yet, the specific contribution of mRNA binding proteins (mRBPs) to melanoma development remains unclear. Here we identify a cluster of melanoma-enriched genes under the control of CUGBP Elav-like family member 1 (CELF1). CELF1 was discovered with a distinct prognostic value in melanoma after mining the genomic landscape of the 692 known mRBPs across different cancer types. Genome-wide transcriptomic, proteomic, and RNA-immunoprecipitation studies, together with loss-of-function analyses in cell lines, and histopathological evaluation in clinical biopsies, revealed an intricate repertoire of CELF1-RNA interactors with minimal overlap with other malignancies. This systems approach uncovered the oncogene DEK as an unexpected target and downstream effector of CELF1. Importantly, CELF1 and DEK were found to represent early-induced melanoma genes and adverse indicators of overall patient survival. These results underscore novel roles of CELF1 in melanoma, illustrating tumor type-restricted functions of RBPs in cancer.",

author = "Metehan Cifdaloz and Lisa Osterloh and Osvaldo Gra{\~n}a and Erica Riveiro-Falkenbach and Pilar Xim{\'e}nez-Emb{\'u}n and Javier Mu{\~n}oz and Cristina Tejedo and Calvo, {Tonantzin G.} and Panagiotis Karras and David Olmeda and Bel{\'e}n Mi{\~n}ana and Gonzalo G{\'o}mez-L{\'o}pez and Estela Ca{\~n}on and Eduardo Eyras and Haihong Guo and Ferdinand Kappes and Ortiz-Romero, {Pablo L.} and Rodr{\'i}guez-Peralto, {Jose L.} and Diego Meg{\'i}as and Juan Valc{\'a}rcel and Soengas, {Mar{\'i}a S.}",

note = "Funding Information: The authors thank the colleagues in the CNIO Melanoma Group, in particular Eva P{\'e}rez-Guijarro, Ra{\'u}l Martinez, {\'A}ngel Colmenar, Direna Alonso-Curbelo and David S{\'a}enz for their help and support; Manuel P{\'e}rez from CNIO Confocal Microscopy Unit for immunofluorescent image capture, and the i+12 Biobank of the Hospital 12 de Octubre for providing melanoma patient samples. We also thank Endre Sebestyen for help with genomic analyses of mRBPs in cancer cells; as well as Jos{\'e} A Esteban (CBMSO, Madrid), for critical reading of this manuscript. M.S.S. was funded by Marat{\'o} TVE, Consolider RNAREG (CSD2009-00080), and SAF2014-56868-R (Spanish Ministry of Economy and Innovation). J.V. was funded by Fundaci{\'o}n Bot{\'i}n, Banco de Santander through its Santander Universities Global Division, Consolider RNAREG (CSD2009-00080), AGAUR and the European Research Council, and acknowledges support of the Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa 2013-2017. J.L.R.-P. was funded by grant FIS 2014/1737, and P.L.O.-R. by FIS 14/1784 from the Spanish Ministry of Health. E.E. was funded by grants BIO2011-23920, Consolider RNAREG (CSD2009-00080), by AGAUR (2014-SGR1121) and by the Sandra Ibarra Foundation for Cancer (FSI2013). The CNIO Proteomics Unit belongs to ProteoRed, PRB2-ISCIII, supported by grant PT13/0001. J.M. was supported by the Ramon y Cajal Programme (MINECO) RYC-2012-10651. H.G. and F.K. were funded by the China Scholarship Council, the Deutsche Forschungsgemeinschaft (DFG KA 2799/1) and the START Program of the Faculty of Medicine of the RWTH Aachen University. M.C. and P.K. were funded by predoctoral fellowships from Fundaci{\'o}n La Caixa, and C.T. from SAF2014-56868-R. E.R.-F. was a recipient of a postdoctoral fellowship from {"}Fundaci{\'o}n Cient{\'i}fica de la Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer{"} and was also supported by FMM-2013/0075 of Fundacion Mutua Madrile{\~n}a. Funding Information: The authors thank the colleagues in the CNIO Melanoma Group, in particular Eva P{\'e}rez-Guijarro, Ra{\'u}l Martinez, {\'A}ngel Colmenar, Direna Alonso-Curbelo and David S{\'a}enz for their help and support; Manuel P{\'e}rez from CNIO Confocal Microscopy Unit for immunofluorescent image capture, and the i+12 Biobank of the Hospital 12 de Octubre for providing melanoma patient samples. We also thank Endre Sebestyen for help with genomic analyses of mRBPs in cancer cells; as well as Jos{\'e} A Esteban (CBMSO, Madrid), for critical reading of this manuscript. M.S.S. was funded by Marat{\'o} TVE, Consolider RNAREG (CSD2009-00080), and SAF2014-56868-R (Spanish Ministry of Economy and Innovation). J.V. was funded by Fundaci{\'o}n Bot{\'i}n, Banco de Santander through its Santander Universities Global Division, Consolider RNAREG (CSD2009-00080), AGAUR and the European Research Council, and acknowledges support of the Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa 2013-2017. J.L.R.-P. was funded by grant FIS 2014/1737, and P.L.O.-R. by FIS 14/1784 from the Spanish Ministry of Health. E.E. was funded by grants BIO2011-23920, Consolider RNAREG (CSD2009-00080), by AGAUR (2014-SGR1121) and by the Sandra Ibarra Foundation for Cancer (FSI2013). The CNIO Proteomics Unit belongs to ProteoRed, PRB2-ISCIII, supported by grant PT13/0001. J.M. was supported by the Ramon y Cajal Programme (MINECO) RYC-2012-10651. H.G. and F.K. were funded by the China Scholarship Council, the Deutsche Forschungsgemeinschaft (DFG KA 2799/1) and the START Program of the Faculty of Medicine of the RWTH Aachen University. M.C. and P.K. were funded by predoctoral fellowships from Fundaci{\'o}n La Caixa, and C.T. from SAF2014-56868-R. E.R.-F. was a recipient of a postdoctoral fellowship from “Fundaci{\'o}n Cient{\'i}fica de la Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer” and was also supported by FMM-2013/0075 of Fundacion Mutua Madrile{\~n}a. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-02353-y",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

number = "1",

}

Cifdaloz, M, Osterloh, L, Graña, O, Riveiro-Falkenbach, E, Ximénez-Embún, P, Muñoz, J, Tejedo, C, Calvo, TG, Karras, P, Olmeda, D, Miñana, B, Gómez-López, G, Cañon, E, Eyras, E, Guo, H, Kappes, F, Ortiz-Romero, PL, Rodríguez-Peralto, JL, Megías, D, Valcárcel, J & Soengas, MS 2017, 'Systems analysis identifies melanoma-enriched pro-oncogenic networks controlled by the RNA binding protein CELF1', Nature Communications, vol. 8, no. 1, 2249. https://doi.org/10.1038/s41467-017-02353-y

TY - JOUR

T1 - Systems analysis identifies melanoma-enriched pro-oncogenic networks controlled by the RNA binding protein CELF1

AU - Cifdaloz, Metehan

AU - Osterloh, Lisa

AU - Graña, Osvaldo

AU - Riveiro-Falkenbach, Erica

AU - Ximénez-Embún, Pilar

AU - Muñoz, Javier

AU - Tejedo, Cristina

AU - Calvo, Tonantzin G.

AU - Karras, Panagiotis

AU - Olmeda, David

AU - Miñana, Belén

AU - Gómez-López, Gonzalo

AU - Cañon, Estela

AU - Eyras, Eduardo

AU - Guo, Haihong

AU - Kappes, Ferdinand

AU - Ortiz-Romero, Pablo L.

AU - Rodríguez-Peralto, Jose L.

AU - Megías, Diego

AU - Valcárcel, Juan

AU - Soengas, María S.

N1 - Funding Information: The authors thank the colleagues in the CNIO Melanoma Group, in particular Eva Pérez-Guijarro, Raúl Martinez, Ángel Colmenar, Direna Alonso-Curbelo and David Sáenz for their help and support; Manuel Pérez from CNIO Confocal Microscopy Unit for immunofluorescent image capture, and the i+12 Biobank of the Hospital 12 de Octubre for providing melanoma patient samples. We also thank Endre Sebestyen for help with genomic analyses of mRBPs in cancer cells; as well as José A Esteban (CBMSO, Madrid), for critical reading of this manuscript. M.S.S. was funded by Marató TVE, Consolider RNAREG (CSD2009-00080), and SAF2014-56868-R (Spanish Ministry of Economy and Innovation). J.V. was funded by Fundación Botín, Banco de Santander through its Santander Universities Global Division, Consolider RNAREG (CSD2009-00080), AGAUR and the European Research Council, and acknowledges support of the Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa 2013-2017. J.L.R.-P. was funded by grant FIS 2014/1737, and P.L.O.-R. by FIS 14/1784 from the Spanish Ministry of Health. E.E. was funded by grants BIO2011-23920, Consolider RNAREG (CSD2009-00080), by AGAUR (2014-SGR1121) and by the Sandra Ibarra Foundation for Cancer (FSI2013). The CNIO Proteomics Unit belongs to ProteoRed, PRB2-ISCIII, supported by grant PT13/0001. J.M. was supported by the Ramon y Cajal Programme (MINECO) RYC-2012-10651. H.G. and F.K. were funded by the China Scholarship Council, the Deutsche Forschungsgemeinschaft (DFG KA 2799/1) and the START Program of the Faculty of Medicine of the RWTH Aachen University. M.C. and P.K. were funded by predoctoral fellowships from Fundación La Caixa, and C.T. from SAF2014-56868-R. E.R.-F. was a recipient of a postdoctoral fellowship from "Fundación Científica de la Asociación Española Contra el Cáncer" and was also supported by FMM-2013/0075 of Fundacion Mutua Madrileña. Funding Information: The authors thank the colleagues in the CNIO Melanoma Group, in particular Eva Pérez-Guijarro, Raúl Martinez, Ángel Colmenar, Direna Alonso-Curbelo and David Sáenz for their help and support; Manuel Pérez from CNIO Confocal Microscopy Unit for immunofluorescent image capture, and the i+12 Biobank of the Hospital 12 de Octubre for providing melanoma patient samples. We also thank Endre Sebestyen for help with genomic analyses of mRBPs in cancer cells; as well as José A Esteban (CBMSO, Madrid), for critical reading of this manuscript. M.S.S. was funded by Marató TVE, Consolider RNAREG (CSD2009-00080), and SAF2014-56868-R (Spanish Ministry of Economy and Innovation). J.V. was funded by Fundación Botín, Banco de Santander through its Santander Universities Global Division, Consolider RNAREG (CSD2009-00080), AGAUR and the European Research Council, and acknowledges support of the Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa 2013-2017. J.L.R.-P. was funded by grant FIS 2014/1737, and P.L.O.-R. by FIS 14/1784 from the Spanish Ministry of Health. E.E. was funded by grants BIO2011-23920, Consolider RNAREG (CSD2009-00080), by AGAUR (2014-SGR1121) and by the Sandra Ibarra Foundation for Cancer (FSI2013). The CNIO Proteomics Unit belongs to ProteoRed, PRB2-ISCIII, supported by grant PT13/0001. J.M. was supported by the Ramon y Cajal Programme (MINECO) RYC-2012-10651. H.G. and F.K. were funded by the China Scholarship Council, the Deutsche Forschungsgemeinschaft (DFG KA 2799/1) and the START Program of the Faculty of Medicine of the RWTH Aachen University. M.C. and P.K. were funded by predoctoral fellowships from Fundación La Caixa, and C.T. from SAF2014-56868-R. E.R.-F. was a recipient of a postdoctoral fellowship from “Fundación Científica de la Asociación Española Contra el Cáncer” and was also supported by FMM-2013/0075 of Fundacion Mutua Madrileña. Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Melanomas are well-known for their altered mRNA expression profiles. Yet, the specific contribution of mRNA binding proteins (mRBPs) to melanoma development remains unclear. Here we identify a cluster of melanoma-enriched genes under the control of CUGBP Elav-like family member 1 (CELF1). CELF1 was discovered with a distinct prognostic value in melanoma after mining the genomic landscape of the 692 known mRBPs across different cancer types. Genome-wide transcriptomic, proteomic, and RNA-immunoprecipitation studies, together with loss-of-function analyses in cell lines, and histopathological evaluation in clinical biopsies, revealed an intricate repertoire of CELF1-RNA interactors with minimal overlap with other malignancies. This systems approach uncovered the oncogene DEK as an unexpected target and downstream effector of CELF1. Importantly, CELF1 and DEK were found to represent early-induced melanoma genes and adverse indicators of overall patient survival. These results underscore novel roles of CELF1 in melanoma, illustrating tumor type-restricted functions of RBPs in cancer.

AB - Melanomas are well-known for their altered mRNA expression profiles. Yet, the specific contribution of mRNA binding proteins (mRBPs) to melanoma development remains unclear. Here we identify a cluster of melanoma-enriched genes under the control of CUGBP Elav-like family member 1 (CELF1). CELF1 was discovered with a distinct prognostic value in melanoma after mining the genomic landscape of the 692 known mRBPs across different cancer types. Genome-wide transcriptomic, proteomic, and RNA-immunoprecipitation studies, together with loss-of-function analyses in cell lines, and histopathological evaluation in clinical biopsies, revealed an intricate repertoire of CELF1-RNA interactors with minimal overlap with other malignancies. This systems approach uncovered the oncogene DEK as an unexpected target and downstream effector of CELF1. Importantly, CELF1 and DEK were found to represent early-induced melanoma genes and adverse indicators of overall patient survival. These results underscore novel roles of CELF1 in melanoma, illustrating tumor type-restricted functions of RBPs in cancer.

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U2 - 10.1038/s41467-017-02353-y

DO - 10.1038/s41467-017-02353-y

M3 - Article

C2 - 29269732

AN - SCOPUS:85042387158

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2249

ER -

Systems analysis identifies melanoma-enriched pro-oncogenic networks controlled by the RNA binding protein CELF1

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